16, 17-cyclic acetals of 16 beta-mercapto-17 beta-hydroxy estrogen derivatives and intermediates in the preparation thereof



3,105,069 16,17-CYCLIC ACETALS QB 165-MERCAPTO-17B- HYDROXY ESTRQGEN DERIVATIVES AND INTERMEDIATES IV THE PREEARATION THEREOF Taichiro Komeno, Sumiyoshi-ku, Osaka-shi, and Norio Tokutake, Nada-kn, Kobe-sin, Japan, assignors to Shionogi & (10., Ltd., Osaka, Japan No Drawing. Filed Aug. 10, 1%2, Ser. No. 216,056

6 Claims. (Cl. 266-23955) This invention relates to 3-alkoxy-l6fl-mercapto-l7/3- hydroxy-1,3,5(l)-estratniene 16,17-cyclic acetals represented by the following formula:

% oi ROQU wherein R and R each represents lower alkyl (e.g. methyl, ethyl, propyl, butyl) and R" represents hydrogen or lower alkyl (e.g. methyl, ethyl, propyl, butyl).

It is an object of this invention to embody 3-alkoxy-16fimercapto-17B-hydroxy-l,3,5(10)-estratriene 16,17 cyclic acetals. Another object is to embody the steroidal cyclic acetals having pharmacological activities. A further object is to embody a synthetic method for preparing the steroidal cyclic acetals. These and other objects will be apparent to those skilled in the art to which this invention pertains from the subsequent description.

The method of this invention is representable by the following scheme:

Step II 3', l g Patented Sept. 24, 1 963 ice iodine), A represents lower alkanoyl (e.g. acetyl, propionyl, butyroyl) or lower alkoxythiocarbonyl (e.g. methoxythiocarbonyl, ethoxythiocarbonyl, propoxythiocarbonyl), R, R and R" each has the same significance as designated above and the ripple mark (5) represents aor ,B-configuration.

The starting material of this invention is 3-alkoXy-16- halogeno-17-oXo-l,3,5(10)-estratriene of Formula I. The lo-haloestratriene I consists of the 16u-haloestratriene and the 16/3-haloestratriene, each being representable by the following 7 formula:

wherein R and X each has the same significance as designated above. The l6a.-haloestratriene la can be prepared from estrone (3-hydroxy-l7-oxo-1,3,5(l0)-estratriene) in a conventional manner [W. S. Johnson et al.: J. Am. Chem. Soc., 79, p. 2005 (1957); G. P. Mueller et al.: I. Am. Chem. Soc., 80, p. 1769 (1958)]. The 16a-haloestratn'ene Ia can be readily converted into the 1613- haloestratriene Ib according to a per se conventional procedure, i.e. by the treatment of the former with alumina or dimethylformamide and lithium bromide.

In the finst step, the l6-haloestratriene I is reacted substantially with a sulfur-containing organic acid such as thioalkanoic acid (e.g. thioacetic acid, thiopropionic acid, thiobutyric acid) and alkyldithio carbonic acid (e.g. methyldithiocarbonic acid, ethyldithiocarbonic acid, propyldithiocarbonic acid). Usually, the reaction is carried out by treating the l6-haloestratriene I with an alkali metal salt of the said sulfur-containing organic acid (e.g. sodium thioacetate, potassium thioacetate, potassium thiopropionate, potassium thiobutyrate, potassium methylditlliocarbonate, sodium ethyldithioca'rbonate, potassium ethyldithiocarbonate, sodium propyldithiocarbonate, potassium propyldithiocarbonate) in a suitable medium (e.g. acetone, ether, dioxane, tetrahydrofuran) at room temperature for several hours.

In the second step, the resultant 16 substituted thioestratriene II is reduced with an alkali metal hydride (e.g. lithium aluminum hydride, lithium borohydride, sodium borohydride). The reaction is usually carried out by treating the 16-substituted thioestratriene II With the said reducing agent in a suitable medium (e.g. ether, dioxane, tetrahydrofuran, benzene), if necessary, while heating.

In the third step, the. resulting 16-mercaptoestratniene 111 is condensed with a carbonyl compound such as alkanoyl aldehyde '(e.g. acetaldehyde, .propionaldehyde, butyraldehyde) and dialkyl ketone (e.g. acetone, methyl ethyl ketone, diethyl ketone, methyl butyl ketone, dipropyl ketone). The reaction can be performed by heating the l-mercaptoestratriene III with the said carbonyl compound in the presence of an acidic catalyst (e.g. p-toluenesulfonic acid, sulfuric acid).

Although the method of this invention is hereinbefore illustrated step by step, these steps may be executed successively without the isolation of the product in each step, especially in the case of that the prepared intermediate is not stable. For instance, the 16-mercaptoestratriene III is relatively unstable and preferred to be subjected to the reaction in the subsequent step without its isolation from the reaction mixture. V

' The final products of this invention are 3-alkoxy-16/3- mercapto-17 3-hydroxy-1,3,5 (10)-estratriene 16,17 cyclic acetalsrof Formula IV. The steroidal cyclic acetals IV show a variety of pharmacological activities such as catabolic activity, uterotropic activity and anti-DOCA (desoxycorticosterone acetate) activity. For instance, S-methoxy 16f mercapto 17B hydroxy-1,3,5(10)-estratriene 16,17-acetonide (I, R=R':R=CH significantly decreased the weights of liver, kidney, spleen, seminal vesicles, ventral prostates, epididymal fat pad, perireal fat pad of male mice and increased the Weights of uterus and pituitary of female mice, when subcutaneously administered. In the same test, the significant reduction of the body weight gain was observed in male mice, but not in female mice. The other products of this invention also show the similar action. Thus, the steroidal cyclic acetals IV are useful, for instance, as catabolic agents, uterotropic agents and fat loosing agents.

The following examples set forth illustratively presentlypreferred embodiments of the invention.

In the examples, the abbreviations have the following significances: mg, milligram(s); ml., millilitrefis); Anal. calcd., analysis calculated; and C., degrees Centigrade. Other abbreviations have conventional significances.

Example I OHaO- i I A suspension a of 3-methoxy-16u-bromo-17-oxo-1,3, w5('1())-estratriene (142 mg.) and potassium thioacetate (80 mg.) in acetone (6 ml.) is stirred for 3.5 hours at room temperature (10 to (3.). Adding water to the CHaO- i reaction mixture, the precipitate is collected by filtration, dried and crystallized from methanol. The crude crystals are recrystallized from acetone-methanol (5:1) to give 3-rnethoxy 16s acetylthio-17-ox0-1,3,5(10) estratriene (124 mg.) as White scales melting at 186 to 187 C. [a] +l54.9i2 (chloroform).

Anal. calcd. for (3 1-1 0 82 C, 70.35; H, 7.31; S, 8.94. Found: (3,7034; H, 7.40; S, 8.94.

Example 2 A solution of 3-methoxy-16u.-bromo-,17-oxo-1,3,5(10)- estratriene (200mg) in acetone is treated with alumina and, after 60 hours, eluated to give 3-methoxy-16/8-bromo- 17-oxo-1,3,5(10)-estratriene (40 mg).

A suspension of 3-methoxy-16/8-bromo-17-oxo-L3,

5(l0)-estratriene (24 mg.) and potassium thioacetate (15 mg.) in acetone (3 ml.) is stirred for 3.5 hours at room' temperature (10 to 25 C.). Adding water to the reaction mixture, the precipitate is collected by filtration, dried and crystallized from acetone-methanol (5: 1) to give S-inethoxy-l 6 3-acetylthio-17-oxo-1,3,5( 10) -estratriene 18 mg.) as white crystals melting at 184 to 187 C.

Example 3 soooH;

To a suspension of lithium aluminum hydride mg.) in anhydrous ether (12 ml.), there is added dropwise a solution of 3-methoxy-16fi-acetylthio-17-oxo-1,3,5(10)- estratriene (260 mg.) intetrahydrofuran (30 ml.) while stirring at room temperature (10 to 25 C.) in 10 minutes. Then, the resultant solution is refluxed for 3.5 hours.

Adding water to the reaction mixture, the precipitate is 1 treated with dilute hydrochloric acid. The ether layer is dried over anhydrous sodium sulfate and the ether isremoved to give the residue containing 3-methoxy-16l3- mercapto-17,8 -hydroxy-1,3,5 10) -estratriene.

To the above-obtained residue, there are added p-toluenesulfonic acid (20 mg.) and'acetone (10 ml.), and

the resultant mixture is refluxed for 4 hours under mois- 1 Anal. calcd. for C H O S: C, 73.70; H, 8.43; S, 8.94.

Found: C, 74.03; H, 8.57; S, 8.86.

What is claimed is: 1. A compound having the following formula:

wherein R and R each represents lower alkyl and R" represents a member selected from the group consisting of hydrogen and lower alkyl.

2. 3-methoxy 16p mercapto17-hydroxy-1,3,5(10)- estratriene 16,17-acetonide.

3. A compound having the following formula:

wherein R represents lower alkyl.

4; 3-methoxy mercapto--hydroxy-1,3,5(10)- estratriene.

5. A compound having the following formula:

wherein R represents lower alkyl and A represents a member selected from the group consisting of lower alkanoyl and lower alkoxythiocarbonyl.

6. 3-methoxy 16,3 acetylthio-17-oxo-1,3,5(10)-estratriene.

No references cited. 

1. A COMPOUND HAVING THE FOLLOWING FORMULA: 